An excellent review article by Edward W. Boyer, MD, PhD, in the New England Journal of Medicine discusses the management of life-threatening overdose from opioid analgesics [Boyer 2012]. He describes essential principles and practices that every healthcare provider, as well as educated patients, absolutely must know about — including some surprising revelations.
Increasing incidents of opioid analgesic overdose have become a major issue of concern, and the variety of opioid agents used in pain management — with their different formulations, characteristics, and duration of action — makes this a complex subject. Yet, Boyer stresses that, “Published guidelines for the management of opioid intoxication were developed on the basis of data from patients with heroin overdose and should not be applied to patients with opioid analgesic overdose.”
Boyer — from the Department of Emergency Medicine, University of Massachusetts Medical Center — suggests that three principles are essential for an understanding of opioid analgesic toxicity: 1) multiple organ systems may be involved in the life-threatening effects of overdose, 2) normal pharmacokinetic properties of opioids may be disrupted during overdose, which can dramatically prolong intoxications, and 3) duration of toxic effects vary widely among opioid formulations and failing to recognize such variation can lead to inappropriate treatment decisions with potentially lethal outcomes. Following are important details from his paper to consider….
Further General Principles
- Patients with chronic pain often have coexisting psychiatric disorders, and these patients are likely to be treated with higher doses of opioids plus medications for anxiety or depression (eg, benzodiazepines and others) that might increase overdose risk.
- Tolerance of respiratory depression develops at a slower pace than opioid-analgesic tolerance and, over time, this delay narrows, or lessens, the therapeutic index [the ratio of a therapeutic amount of opioid compared with the toxic or lethal amount]. Paradoxically, even patients with a long history of opioid analgesic use can unexpectedly become at increased risk for respiratory depression, Boyer suggests.
- Surprisingly, the pharmacokinetics of particular opioids — absorption, onset of action, clearance, and biologic half-life — are often irrelevant in overdose. However, quantity of opioids ingested and/or route of administration if abused (eg, snorting, injecting, patch misuse) can be critically important factors.
- In the case of overdose [and presumably in overmedication], excessive quantities of opioid can overwhelm normal enzymatic processes of metabolism. When this happen, small increases in drug dose can incur exceedingly large increases in plasma concentration and intoxication. Also, a constant amount rather than a constant proportion of drug is eliminated per unit of time, thus extending metabolism. Together, these “toxicokinetic effects” can produce opioid toxicity that may be severe, delayed in onset, and prolonged as compared with expected therapeutic actions.
Clinical Manifestations & Diagnosis
- Classic signs of opioid overdose are hypopnea or apnea [slow or intermittently stopped breathing], stupor, and miosis [constricted pupils], but these are not all consistently present. Miosis alone is insufficient to infer opioid intoxication, and poisoning from meperidine, propoxyphene, or tramadol may be associated with normally reactive [mydriatic] pupils.
- Respiratory depression is the most representative sign of opioid intoxication, typically characterized by a respiratory rate of ≤12 breaths per minute in a person who is not in deep sleep. With other agents sometimes taken by patients with pain — antipsychotic drugs, anticonvulsants, sedative hypnotics, and ethanol [alcohol] — respiratory depression may be absent during overdose; yet, these agents may cause miosis and coma.
- Overdose victims may become hypothermic [low body temperature] from lying unresponsively for a long time in a cool environment or from misguided attempts of bystanders at reviving the person with cold water.
- Additionally, lying immobile in an opioid-induced stupor for a prolonged period of time may incur rhabdomyolysis [breakdown of muscle fibers], myoglobinuric renal failure [tubule obstruction due to myoglobin released from muscle fibers], and compartment syndrome [increased pressure in a muscle compartment that can lead to muscle, nerve, and circulatory damage]. In themselves, these can be life-threatening conditions and should be taken into account by emergency care providers.
- Additional abnormalities in opioid analgesic overdose may include elevated serum aminotransferase levels in association with liver damage due to acetaminophen poisoning [such as when opioids are combined with APAP] or hypoxemia [oxygen deficiency in arterial blood], and seizures have been associated with overdose of tramadol, propoxyphene, and meperidine.
- Opioid overdose in a child is often characterized by delayed onset, unexpectedly severe poisoning, and prolonged toxic effects. This is due to rates of drug absorption, distribution into the central nervous system, and metabolism in children that differ from those in adults, Boyer notes.
- Overdose in elderly persons may be complicated by preexisting conditions, such as renal insufficiency, chronic obstructive pulmonary disease, or sleep apnea. Also, age-related changes in body composition [influencing reduced binding of drug to plasma proteins] and diminished hepatic flow may cause unexpected and persistent opioid analgesic intoxication.
- In patients with severe respiratory depression and suspected opioid overdose, restoration of breathing —ventilation and oxygenation — takes precedence over fact gathering or diagnostic testing to ascertain exact causes and quantities of the culpable agents.
- Patients with severe respiratory depression need a pharmacologic or mechanical stimulus in order to breath. For those with stupor and respiratory rates ≤12 breath per minute ventilation via a bag-valve mask may help to diminish hypercarbia [excessive carbon dioxide levels] and restore oxygenation. In the unconscious patient in the emergency department orotracheal intubation might be considered for insuring oxygenation and ventilation while protecting against aspiration.
- A simple and effective pharmacologic antidote for opioid overdose is the mu-opioid antagonist naloxone. Its onset of action in adults when administered intravenously is <2 minutes, and its duration of action is 20 to 90 minutes (which is a much shorter period than for most opioids). [Boyer does not mention off-label intranasal administration of naloxone, which would have a similar onset and duration of effect.]
- “Dosing of naloxone is empirical,” Boyer states. The effective dose depends on the amount of opioid analgesic taken by the patient, the type of opioid to be displaced from mu-opioid receptors, the patient’s weight, and the degree to which the opioid has penetrated the central nervous system. Most of this information will be unknown in emergency situations, so clinicians must rely on a pragmatic approach to dosing.
- The initial naloxone dose in adults is 0.04 mg; if there is no response, increasing doses should be administered every 2 to 3 minutes in progressively larger amounts up to a maximum single dose of 15 mg. If there is no relief from respiratory depression at this highest dose, it is unlikely that opioid overdose is causative of the patient’s distress.
- Children — up to 5 years of age or 20 kg body weight — who accidentally ingest opioid analgesics often consume a much greater dose per kilogram of body weight than adults; therefore, children may require significantly larger doses of naloxone than adults to reverse overdose effects [many practitioners are unaware of this].
- The figure (at right, from Boyer 2012, NEJM) shows that, compared with the therapeutic actions of opioid analgesics, toxic effects in the event of overdose usually have a delayed onset (except with immediate release fentanyl) and a much longer duration. Single-dose naloxone effects in reversing overdose are rapid, but of relatively very short duration.
- It is important to note that development of opioid toxicity is usually a delayed response and its reversal by individual naloxone doses is transient. Furthermore, severity of opioid-induced respiratory depression is unrelated to peak concentration of the opioid and its timing cannot be reliably determined in overdose situations.
- Boyer states that, “Naloxone can be administered without compunction in any patient,” including those with opioid dependence in whom precipitated withdrawal of a severe nature might be of concern. In fact, he observes, patients with opioid tolerance and physiologic dependence often have responses to low doses of naloxone that are sufficient to restore breathing and without provoking withdrawal.
- Once the patient is stabilized it could be important to examine the body for opioid patches [fentanyl or buprenorphine] and to inquire about the use of acetaminophen (including products co-formulated with APAP). One or more patches remaining in place will obviously complicate overdose reversal and in the case of acetaminophen hepatotoxicity the administration of N-acetylcysteine may be necessary.
- When the respiratory rate improves after naloxone administration, the patient should be closely observed and monitored for at least 4 to 6 hours. However, an implication in Boyer’s review is that, depending on patient age, physical condition, and the type and amount of opioid analgesic ingested, a much longer period of observation might be advisable.
COMMENTARY: Clearly, opioid analgesic overdose is a multifaceted and life-threatening condition requiring immediate action. Adverse effects may recur or persist long after the urgent crisis has passed. We have strongly advocated for the prescribing of naloxone to all persons prescribed opioid analgesics, so it is on hand for at-home rescue in case of overmedication or overdose toxicity.
For example, see our journal article [here] and the most recent UPDATE on this topic [here]. Additionally, at our Opioid911-Safety website [http://Opioids911.org], we have vital documents for patients and their caregivers, regarding Signs to Watch For – Overmedication or Overdose? and Overdose Emergencies: What to Do Until Help Comes.
The review article by Boyer — unique in specifically and comprehensively addressing overdose due to opioid analgesics — provides some important reminders and cautions…
- Much of what is known about naloxone for overdose reversal is from experiences with heroin abusers, but most opioid analgesics are quite different in terms of their half-life and duration of action. Anecdotal accounts of overdosed heroin users being revived by a single dose of naloxone cannot be generalized to cases involving opioid analgesics.
- In almost all cases, the amount of naloxone prescribed for at-home overdose rescue will be insufficient to deal with the typical recurrence of respiratory depression from opioid analgesics after effects of naloxone have worn off. Emergency services must always be called at the outset.
- Initial dosing of naloxone, whether by home caregivers or other first-responders, is a stop-gap measure, and in most cases must be followed by repeated naloxone administration and continued observation as needed. Boyer notes that clinicians who are largely experienced in treating heroin overdose may wrongly believe that single-dose naloxone will prevent a recurrence of opioid analgesic toxicity.
- However, it seems obvious from Boyer’s explanations that some naloxone is better than none at all, and even in the most severe cases of overdose a small amount might relieve fatal respiratory depression sufficiently and long enough for emergency help to arrive.
- Also, it is important to remember that drug overdoses in pain-treated persons often are mixed intoxications, involving more than a single opioid agent and/or adjunctive agents (eg, benzodiazepines), which can complicate the crisis situation and make the need for followup medical care very important.
- Finally, overdose care for a child or elderly patient may require special considerations in naloxone dosing, and followup consultation with specialists might be recommended.
Past associations of naloxone with treating heroin overdose — by emergency services professionals and as advocated by harm reduction programs that primarily serve drug-addicted populations — may be forestalling its broader acceptance and prescription for overdose due to opioid analgesics. Naloxone is known as a drug for saving the lives of “heroin junkies”; it is often not perceived as something that grandma Gussie or uncle Hubert should have on hand just because they have been prescribed opioids for chronic pain. This is misguided thinking, but why else would government agencies, and many healthcare providers, be dragging their feet when it comes to making this life-saving overdose antidote more readily and widely available to the public?
REFERENCE: Boyer EW. Management of Opioid Analgesic Overdose. New Engl J Med. 2012(Jul 12);367(2):146-155 [abstract here].
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